Programmed death 1 ligand 1, also known as CD274, is a member of the B7 family and is a ligand for PD-1. PD-L1 is a type I transmembrane protein with a total of 290 amino acids, including an IgV-like region, an IgC-like region, a transmembrane hydrophobic region, and an intracellular region consisting of 30 amino acids.
Unlike other B7 family molecules, PD-L1 has a negative regulatory effect on immune responses. The study found that PD-L1 is mainly expressed in activated T cells, B cells, macrophages and dendritic cells. In addition to lymphocytes, PD-L1 is also expressed in other tissues endothelial cells such as thymus, heart, placenta, etc., as well as various non-lymphoids such as melanoma, liver cancer, gastric cancer, renal cell carcinoma, ovarian cancer, colon cancer, breast cancer, esophageal cancer, head and neck cancer, etc. PD-L1 is versatile in regulating autoreactive T, B cells and immune tolerance, and plays a role in peripheral T and B cell responses. The high expression of PD-L1 on tumor cells is associated with poor prognosis in cancer patients.
Programmed death-1 (PD-1), also known as CD279, is a member of the CD28 family. It has two tyrosine residues in the cytoplasmic region. One located near the N-terminus is in the immunoreceptor tyrosine-based inhibitory motif (ITIM) and another one near the C-terminus is located in the immunoreceptor tyrosine-based switch motif (ITSM). PD-1 is mainly expressed on the surface of activated T lymphocytes, B lymphocytes and macrophages. Under normal conditions, PD-1 can inhibit the function of T lymphocytes and promote the function of Treg, thereby inhibiting autoimmune responses and preventing autoimmune diseases. However, in the occurrence of tumors, PD-L1 expressed by tumor cells combined with PD-1 can promote tumor immune escape by inhibiting lymphocytes. The combination of PD-L1 and PD-1 can lead to a variety of biological changes, leading to immune regulation, such as inhibition of lymphocyte proliferation and activation, inhibition of CD4+ T cell differentiation into Th1 and Th17 cells, inhibition of inflammatory cytokine release, etc.
The successful application of monoclonal antibodies in the detection and bio-targeted treatment of cancer has caused a revolution in cancer treatment. However, the traditional monoclonal antibody (150 kD) molecular mass is too large. It is difficult for monoclonal antibody to penetrate the tissue, resulting in a low effective concentration of the tumor area, and the therapeutic effect is insufficient; the traditional antibody has high immunogenicity, and the modified antibody is difficult to reach the original affinity. In addition, the long-term development of fully humanized traditional antibodies, high production costs, insufficient stability and many other factors limit its application and popularity in the clinic.
Nanobodies are currently the smallest antibody molecules with a molecular weight of 1/10 of a normal antibody. In addition to the antigenic reactivity of monoclonal antibodies, nano-antibodies possess some unique functional properties, such as small molecular mass, strong stability, good solubility, easy expression, weak immunogenicity, strong penetrability, strong targeting, simple in humanization, low in preparation cost, etc. It almost completely overcomes the shortcomings of traditional antibody long-term development cycle, low stability and harsh storage conditions.
However, there is currently no satisfactory nanobody for PD-L1 in the field. Therefore, there is an urgent need in the field to develop new and specific nanobodies that are effective against PD-L1.